Available online at www.sciencedirect.com Respiratory Physiology & Neurobiology 159 (2007) 301–310 Interstitial matrix and transendothelial fluxes in normal lung Daniela Negrini ∗ , Alberto Passi Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Universit` a degli Studi dell’Insubria, Via Dunant 5, 21100 Varese, Italy Accepted 5 April 2007 Abstract Pulmonary gas exchange critically depends upon the hydration state and the thinness of the interstitial tissue layer within the alveolo-capillary barrier. In the interstitium, fluid freely moving within the fibrous extracellular matrix equilibrates with water chemically interacting with hyaluronic acid and proteoglycans, the non-fibrillar components of the matrix. The integrity of the macromolecular assembly of the tissue matrix is required in all processes involved in establishing and maintaining the adequate interstitial tissue fluid volume, by providing: (a) a stiff three dimensional fibrous scaffold, functioning as an efficient safety factor to oppose fluid filtration into the tissue and preventing tissue fluid accumulation; (b) a restrictive perivascular and interstitial sieve with respect to plasma proteins; (c) a mechanical support to initial lymphatics. Therefore, disturbances of the deposition and/or turnover of the matrix and/or of its three dimensional architecture and composition are invariably accompanied by profound changes of the steady state tissue fluid dynamics, eventually evolving towards severe lung disease. © 2007 Elsevier B.V. All rights reserved. Keywords: Pulmonary interstitial fluid; Interstitial fibrous matrix; Albumin exclusion; Interstitial protein concentration 1. The pulmonary interstitial space The mammalian respiratory system has evolved to allow ade- quate exchange of respiratory gasses between the “external” environment, i.e. air in the alveolus, and the “milieu interior”, represented by the extracellular plasma compartment. The pul- monary interstitial space interposed between the endothelial and the epithelial layers, is composed of a three dimensional scaf- fold of insoluble macromolecules arranged around the interstitial cells (mostly fibroblasts and macrophages) and filled with a solu- tion of soluble solutes of variable molecular weight, from salts to large molecular weight plasma proteins, dispersed in a water environment. The three dimensional architecture of the intersti- tium supports the vascular and lymphatic endothelial cells as well as the alveolar epithelial cells, partly determines the per- meability to water and solutes of the respective barriers and accounts for the mechanical strength of the lung parenchyma. The pulmonary interstitium plays a crucial role in modulating respiratory gas exchanges. In fact, diffusive fluxes ( ˙ V gas ) of O 2 and/or CO 2 through the alveolo-capillary barrier of given surface ∗ Corresponding author. Tel.: +39 0332 397104; fax: +39 0332 397119. E-mail address: Daniela.Negrini@uninsubria.it (D. Negrini). (S) and thickness (τ ), are given by: ˙ V gas = K gas S τ P gas (1) where K gas and P gas represent the membrane Krogh diffusion coefficient and the gas partial pressure difference across the bar- rier, respectively. While the alveolar epithelial and endothelial cells are not subject to significant changes in their thickness, in contrast the interposed interstitial space is able to expand, leading to an increased thickness of the alveolo-capillary bar- rier and, as predicted by Eq. (1), to an impairment of pulmonary gas exchanges. Expansion of the interstitial tissue volume may depend upon an altered deposition of interstitial tissue fibres, as in pulmonary fibrosis. Alternatively, an increased thickness of the alveolo-capillary barrier may reflect abnormal accumula- tion of the extracellular interstitial fluid. In the normal lung, in face of the frequent changes in cardiovascular and respi- ratory parameters (e.g. pulmonary arterial pressure, cardiac output, body position, ventilation, etc.), pulmonary interstitial fluid volume is tightly minimized as a results of the balance between: (a) the selective sieve operated by the microvas- culature wall on the transendothelial fluid and solute fluxes; (b) the mechanical response of the interstitial tissue fibres to fluid accumulation; (c) fluid and solute clearance through pul- monary lymphatic vessels. This Review aims at describing how 1569-9048/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2007.04.003